Mechanisms of ERV‐activated interferon (IFN) production in autoimmunity. The human genome harbors retroelements, such as LINE‐1. They can be reverse transcribed into DNA and metabolized by TREX1 (the three prime repair exonuclease 1 gene), which is deficient in patients with Aicardi‐Goutières syndrome and chilblain lupus . Increased transcription of LINE‐1 is now recognized as an important trigger of IFN production, which is mediated through RNA sensing, and it involves signal transduction through TLR‐7/TLR‐8, cGMP–cAMP synthase (cGAS), retinoic acid–inducible gene 1 (RIG‐1), and NF‐κB. Alternatively, reverse transcribed ERV DNA is recognized via TLR‐9, which also traffics through endosomes . Moreover, mitochondrial oxidative stress activates the mitochondrial antiviral signaling protein (MAVS), which acts as an amplifier of RIG‐1 activation during IFN signaling . Oxidative stress also causes DNA hypomethylation , a process that underlies increased LINE‐1 expression . In addition to promoting nucleic acid–driven IFN production, ERV Gag‐encoded proteins, such as HRES‐1/p28, or the LINE‐1 p40 protein may also contribute to autoimmunity via molecular mimicry . See Figure 1 for other definitions.